Prenatal diagnosis is achieved in almost 30% of cases (1). It is usually made during the third trimester. In the sagittal plane, the ultrasound appearance of a VGM is characterized by a hypoechogenic midline tubular structure localized in the posterior part of the third ventricular, described as a “comet tail” or “keyhole sign.” Doppler imaging shows turbulent arterial and venous flow (1, 18). In the coronal plane, a VGM appears as a round cystic structure. The differential diagnosis includes arachnoid cysts, porencephalic cysts, choroidal papillomas, and brain tumors; the use of color Doppler can easily help differentiate these conditions (1, 18, 19, 21, 23, 26, 29). The two most common prenatal features are fetal hydrocephalus and fetal cardiomegaly.

Hydrocephalus is present in almost 40% of cases and results either from high venous pressure, which interferes with the cerebrospinal fluid (CSF) drainage, or from the compressive effect of the malformation. In our study, the presence of prenatal hydrocephalus was associated with a poor outcome (15, 39).

Cardiomegaly is present in almost 60% of cases. The increment of the cardio thorax index is mainly due to the dilatation of the superior vena cava and the right ventricle, probably due to the high venous return from the brain (40). Cardiac involvement is less pronounced in fetal life compared to the postnatal period due to the low vascular resistance of VGMs being balanced by the low resistance of the uteroplacental unit (3, 41).

A prenatal neuroradiological, cardiological, and neonatological evaluation should be offered to explain the possible complications and postnatal management to the pregnant woman. We also advise a genetic consultation. A fetal ultrasound with fetal echocardiography should be offered at least every 2 weeks (3, 39, 40). The type of birth should be personalized for each case; in the absence of cardiological dysfunction and no other contraindications, vaginal delivery can be performed safely (1). From our review, vaginal delivery was performed in almost one-third of cases.

In previous studies, the presence of fetal cardiomegaly and ventriculomegaly were associated with poor outcomes (3, 40, 42, 43). Our prenatal data overlaps with those from previous studies; in our review, the presence of prenatal cardiomegaly, heart failure, and hydrocephalus was associated with a worse postnatal outcome, and none of the newborns discharged home with elective embolization had presented these conditions prenatally. When these features are present, we recommend delivering the newborn in a fully equipped center.

When there is a suspicion of a VGM, performing a fetal MRI should always be advised for a better study of brain anatomy and to predict the clinical outcome (17, 32, 33). The role of MRI has many clinical impacts. First, MRI can better define the VGM anatomy and its dimensions; in addition, it gives information about the presence of hydrocephalus and the development of brain parenchyma, including the presence of diffuse brain injury or hemorrhage, which may impact future clinical management. Arko et al. have shown that in fetal and postnatal MRI, the mediolateral diameter or cross-sectional area of the straight or falcine sinus at its shortest section serves as a predictor of neonatal mortality and an indication for intervention. The lesser constriction of this point was associated with neonatal-onset VGMs and thus a more severe outcome (44). Saliou et al. described how the presence of “pseudofeeders” and increased CSF volume, defined by an Evans index of >0.31, are predictive of the development of heart failure after birth and of a worse outcome. Pseudofeeders are the cortical branches of the MCA and are not choroidal arteries; they supply the brain parenchyma and are not the vessels involved in the VGM (45). The prenatal MRI features have not been included in this review due to a lack of data.

From the latest discoveries, the prenatal MRI findings, such as diffuse parenchymal brain injury or hemorrhage, dilatation of the falcine sinus at its shortest section, and the presence of pseudofeeders or an Evans index of >0.31, play a pivotal role in the decision algorithm (44–46).

At birth and during the first hours or days of life, patients with VGMs usually present in good and stable condition. However, instability can develop within hours or days, mainly due to the transition from fetal to postnatal circulation and the type of VGMs. The choroidal type tends to be diagnosed in the newborn due to its hemodynamic impact, while the mural type may be diagnosed after the neonatal period. Newborns with VGMs should be assisted or rapidly transferred to a specialized center where a neuroradiologist, neonatologist, pediatric cardiologist, and neurosurgeon are present (43).

Embolization is the main treatment for VGMs: the approach can be transarterial, transvenous, or both, but transarterial close is the most commonly used method. The transvenous approach is less effective and carries a higher risk of complications (31, 44, 47). Usually, more than one procedure is needed to achieve the occlusion of the malformation, as the amount of parenteral fluid and contrast is limited in newborns and infants (11). Various agents and devices can be used for embolization, including N-butyl cyanoacrylate (NBCA) glue, liquid embolic agents, and coils, with liquid glue being the most frequently used. The main goals of embolization are to reduce cardiovascular stress and high pressure on the brain to favor CSF drainage and allow normal brain development. The timing of embolization is governed by cardiac hemodynamics and the extent of brain involvement (11, 43, 47). Other techniques are microsurgery, radiosurgery, or a combination of several procedures (11, 31, 44, 47).

Lajaunias has proposed “The Bicetre score,” which assesses the cardiological, neurological, hepatic, renal, and respiratory function. If the score is <8, the condition is too severe for embolization; a score between 8 and 12 indicates that the patient is a candidate for urgent treatment, while a score >12 suggests elective treatment should be proposed if the patient is at least 5 months old (43, 48). This score is, however, not yet used, and there is always more focus on prenatal and postnatal predictive markers, including the presence of dilatation of the falcine sinus at its shortest section, the presence of pseudofeeders or an Evans index of >0.31, and prenatal heart failure. In addition, the presence of diffuse parenchymal brain injury or hemorrhage before the procedure, even in the absence of cardiovascular involvement, is a prognostic indicator of a poor outcome. Each case must be analyzed to decide the best approach. In our review, the outcome was negative in newborns who were not eligible for embolization; conversely, more than half of the newborns who underwent embolization survived with good odds of normal development or only mild disability (44–46).

In cases of hemodynamic and brain stability, a pediatric assessment should be performed at least every 2 weeks, with a stable assessment of head circumference, and head CT or MRI should be performed at 4, 8, 16, and 24 weeks (48). Embolization is usually performed around the 5th month (43, 48, 49). This occurs in only 20% of prenatally diagnosed VGMs.

Almost 80% of newborns with VGMs tend to present cardiac insufficiency during the first days of life, with hemodynamic instability being the main cause of death. Lowering pulmonary circle pressure and closing the patent ductus arteriosus (PDA) increase systemic vascular resistance and can trigger cardiac insufficiency. This condition arises due to the volume and pressure overload in the right chambers of the heart. Due to the low vascular resistance in the head, the majority of the ejection fraction is directed toward the brain (the steal effect of VGMs) (40). This phenomenon can cause lactic acidosis and may also cause cardiac and systemic ischemia. Pulmonary hypertension can be present, mainly due to the volume overload in pulmonary arteries (40, 50). On echocardiography, the heart appears structurally normal, but there is cardiomegaly, and the right chambers appear dilated and hypokinetic, while the left chambers are hyperdynamic. Cardiological treatment usually involves diuretics and volume restriction to reduce preload, as well as vasoactive agents, including low-dose epinephrine, dobutamine, and other inotropic agents. In particular, milrinone and levosimendan have been proposed and have shown good results (41, 50–53). A pediatric cardiologist plays a main role in VGM management, and during hospitalization, especially after the embolization, daily assessment is mandatory.

From our review, the overall mortality of prenatally diagnosed VGMs was almost 60%; however, favorable neurological development was achieved in the majority of survivors. Our results are in line with previous studies (3, 29, 42, 43, 46, 54). It is essential to follow up on the neurodevelopment of these patients by evaluating their milestones using approved tools, such as Bayley Scales of Infant or Toddler Development3rd Edition (BSID-III), and neuro-electrophysiological assessments (54).

In the genetic era, it is recommended that all VGM patients should receive a genetic evaluation.

By performing genome-wide linkage analysis, mutations in RASA1, ENG, ACVRL1, ALK1, SMAD4, and EPHB4 have been associated with genetic VGMs. A specific next generation sequencing (NGS) panel for genetic mutations associated with VGMs should be offered prenatally or after birth. Autosomal dominant mutations of RASA1 gene are responsible for almost one-third of VGM cases, followed by EPHB4, which accounts for 10% of VGM cases (2, 54–57). RASA1 encodes for RAS GTPase activating protein1, which enhances the intrinsic GTPase activity. Studies conducted on RASA1 knockout mice have demonstrated how this gene is fundamental to embryonic vessel formation. Heterozygous mutations leading to the loss of function of EPHB4 are linked to genetic non-immune hydrops fetalis in cutaneous capillary malformation-arteriovenous malformation syndrome and recently to VGM development. This is not surprising since EPHB4 is essential for venous development and differentiation (57). ALK1 is a TGF-β receptor that interacts with endoglin encoded by ENG to activate SMAD4; this is one of the main pathways for angiogenesis. Mutations in ALK1 result in type 2 hereditary hemorrhagic telangiectasia; mutations in ENG and SMAD4 result in vascular malformation (54–57).

As reported previously, the transition from fetal to postnatal circulation represents a critical point for VGM patients. To date, few case reports dealing with fetal endovascular treatment with interesting results have been published. Naggara et al. presented a case of a 31-week and 4-day fetus with a novel diagnosis of the VGM. At that time, the fetus exhibited cardiomegaly without heart failure, and the MRI performed at 34 weeks and 5 days revealed a mediolateral diameter of the dilated falcine sinus at its narrowest section measuring 10.4 mm. A transutero embolization was performed using detachable platinum coils at 33 weeks without any complications; this procedure resulted in a reduction of the cardiomegaly and the dilatation of the falcine sinus. Labor was induced at 38 weeks. However, on day 5 of life, an urgent transfemoral arterial endovascular approach was needed for acute heart failure; a second procedure was performed at 2 months of life. At 11 months, normal neural development was observed (58). Orbach et al. presented a case of ultrasound-guided percutaneous, transuterine, transcranial embolization performed on a fetus at 34 weeks and 2 days of gestation. The indication for intervention was a dilated falcine sinus associated with a 99% likelihood of neonatal decompensation. The procedure was uneventful, resulting in a 43% reduction in total cardiac output and a reduction in the caliber of the prosencephalic varix and falcine sinus. However, 2 days later, labor started following premature rupture of membranes. The neonatal outcome was good, and after 30 days, no cardiovascular support was needed (59).